Peripheral neuropathies affect more than 20 million people in the United States. Patients with peripheral neuropathies suffer from debilitating motor and sensory deficits that can cause severe pain and paralysis. Many forms of inherited peripheral neuropathies impair Schwann cell function and result in abnormal myelin production or demyelination, which is thought to be the underlying cause of the motor and sensory deficits. Schwann cells intimately associate with axons to organize peripheral nerves during development and to insulate axons with myelin. The NRG1/ERBB signaling pathway allows for Schwann cells and axons to communicate with each other and provides essential instructions that regulate Schwann cell proliferation, migration and myelination. Modulation of the NRG1/ERBB signaling pathway can restore function to several rodent models of Charcot-Marie-Tooth disease (CMT). Therefore, identifying the mechanisms that control NRG1/ERBB signaling has important implications for the treatment of peripheral neuropathies. Our data from mice and cell culture experiments indicate that the endosome is a critical regulator of ERBB2/3 function during myelination. To investigate the endosomal pathways controlling ERBB2/3 signaling, we have developed mouse models that impair endosomal sorting of internalized cell surface receptors. We have focused on hepatocyte growth factor regulated tyrosine kinase substrate (HGS), which directs the sorting of internalized receptors through the endosome. HGS expression is diminished in two different mouse models of CMT, implicating defective endosomal sorting as a cause for demyelinating neuropathies. Our data now indicate that loss of HGS in Schwann cells replicates many features of inherited peripheral nerve disorders, including motor and sensory deficits and dysmyelination of sciatic nerves. Impairing endosomal function by deleting the Hgs gene specifically in Schwann cells also showed that ERBB2/3 receptor signaling is dependent upon endosomal sorting to activate its downstream signaling pathways. In addition, we have identified a novel endosomal protein complex in Schwann cells that occurs during myelination. To test the hypothesis that endosomal sorting regulates ERBB2/3 function during myelination, Aim 1 will determine the role of endosomal sorting in Schwann cells for the development and function of peripheral nerves, and Aim 2 will determine how endocytic trafficking controls the sorting and signaling of the ERBB2/3 receptors in Schwann cells. To investigate the mechanism regulating ERBB2/3 function in Schwann cells, Aim 3 will determine which HGS interacting protein complexes are required for ERBB2/3 sorting and signaling in Schwann cells. The completion of this proposal is expected to provide novel insights on the endosomal biology of Schwann cells and further our understanding of how endosomal sorting controls ERBB receptor signaling during myelination. Our long-range goals are to determine the regulatory pathways that control endosomal function in Schwann cells in order to identify targets for the treatment of demyelinating diseases such as CMT.